Indane derivatives, process for their preparation, their use as pharmaceuticals and pharmaceutical compositions containing said derivatives

ABSTRACT

The invention provides compounds of formula ##STR1## wherein R 1  and R 2  are alkyl, R 3  is hydrogen, alkyl, alkenyl, phenylalkyl or a group --(CH 2  --CH 2  --O) n  --R 4  in which n is 1 to 3 and R 4  is hydrogen or an acid residue, and the ring A is unsubstituted or substituted, with the proviso that when R 3  is methyl the ring A is substituted. The compounds are useful in the treatment and prophylaxis of allergic conditions.

The present invention relates to new indane derivatives, theirpreparation, their use as pharmaceuticals and pharmaceuticalcompositions containing them.

More particularly the invention provides an indane derivative of formulaI ##STR2## wherein R₁ and R₂, independently, are C₁₋₄ alkyl,

R₃ is hydrogen; C₁₋₄ alkyl; C₃₋₅ alkenyl; C₇₋₁₀ phenylalkyl optionallysubstituted in the phenyl ring by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; ora group of formula (a)

    --(CH.sub.2 --CH.sub.2 --O).sub.n --R.sub.4                (a)

wherein n is an integer of from 1 to 3 and R₄ is hydrogen or aphysiologically-acceptable and -hydrolysable acid residue, and

the ring A is unsubstituted or substituted,

with the proviso that when R₃ is methyl the ring A is substituted,

as well as the salts thereof.

In the present specification and claims halogen means fluorine, chlorineor bromine.

Alkyl and alkoxy radicals in formula I may be branched or straight chainand preferably contain 1 or 2 carbon atoms.

R₁ and R₂ are preferably the same. R₁ and R₂ are especially C₁₋₂ alkyl,more especially methyl.

When R₃ is alkyl, this is preferably C₁₋₂ alkyl or, more preferably,methyl. When R₃ is alkenyl this may be branched or straight chain and isespecially allyl.

When R₃ is phenylalkyl this is preferably benzyl. When the phenyl ringof a phenylalkyl radical R₃ is substituted, there are conveniently 1 or2 substituents. Preferred substituents are halogen, in particularfluorine and bromine, C₁₋₄ alkyl, in particular methyl, and C₁₋₄ alkoxy,in particular methoxy. Preferably the phenyl ring is unsubstituted.

In the group of formula (a), n may be 1, 2 or 3. Preferably n is 1 or 2.

By the term "physiologically-hydrolysable and -acceptable acid residue"is meant an acid residue which is removable by hydrolysis underphysiological conditions and which is itself physiologically acceptable,i.e. non toxic. R₄ in formula (a) may accordingly represent e.g. acarboxylic acyl residue, e.g. acetyl or benzoyl. Preferably R₄ ishydrogen.

Ring A may optionally be substituted, e.g. di- or, preferably,mono-substituted. Preferably ring A is unsubstituted or ismono-substituted. Preferred substituents are fluorine, chlorine, C₁₋₄alkyl, in particular methyl, and C₁₋₄ alkoxy, in particular methoxy.

In a preferred group of compounds of formula I, R₃ is hydrogen or alkyl,most preferably alkyl, and ring A is substituted.

In a second preferred group of compounds of formula I, R₃ is a group offormula (a) and ring A is unsubstituted or substituted.

A group of compounds in accordance with the invention, are those offormula I wherein R₁ and R₂, independently, are C₁₋₄ alkyl, R₃ ishydrogen, C₁₋₄ alkyl, C₃₋₅ alkenyl, C₇₋₁₀ phenylalkyl optionallysubstituted in the phenyl ring by 1 or 2 substituents selected fromfluorine, chlorine, methyl and methoxy, or a group of formula (a)wherein R₄ is hydrogen, and wherein the ring A is optionallymonosubstituted by fluorine, chlorine, C₁₋₄ alkyl or C₁₋₄ alkoxy, withthe proviso that when R₃ is methyl, the ring A is substituted.

The present invention further provides a process for the production of acompound of formula I as defined above, which process comprises

(a) preparing a compound of formula I wherein R₃ is C₁₋₄ alkyl or C₇₋₁₀phenylalkyl optionally substituted in the phenyl ring by halogen, C₁₋₄alkyl or C₁₋₄ alkoxy, by dehydrating a compound of formula II ##STR3##in which R₁ and R₂ are as defined above, the ring A is substituted orunsubstituted and R₃ ' is C₁₋₄ alkyl or C₇₋₁₀ phenylalkyl optionallysubstituted in the phenyl ring by halogen, C₁₋₄ alkyl or C₁₋₄ alkoxy; or

(b) preparing a compound of formula I wherein R₃ is hydrogen, byhydrolysing a compound of formula III ##STR4## in which R₁ and R₂ are asdefined above, the ring A is substituted or unsubstituted and R₅ is C₁₋₄alkyl; or

(c) preparing a compound of formula I wherein R₃ is other than hydrogen,by reacting a compound of formula IV ##STR5## in which R₁ and R₂ are asdefined above and the ring A is substituted or unsubstituted, with acompound of formula V

    R.sub.6 --X                                                (V)

in which R₆ has the meaning given for R₃ above excluding hydrogen, and Xis the acid residue of a reactive ester; or

(d) preparing a compound of formula I wherein R₃ is a group of formula(a) in which R₄ is a physiologically-hydrolysable and -acceptable acidresidue, by esterifying a compound of formula I in which R₃ is a groupof formula (a) wherein R₄ is hydrogen; or

(e) preparing a compound of formula I wherein R₃ is a group of formula(a) in which R₄ is hydrogen, by hydrolyzing a compound of formula Iwherein R₃ is a group of formula (a) in which R₄ is an acid residue, andwhen required recovering the compound of formula I in free base form orin salt form.

The dehydratation according to process (a), may be effected inconventional manner, for example in the presence of a mineral acid, e.g.hydrochloric acid or sulfuric acid in an aqueous or alcoholic medium, orin glacial acetic acid, at temperatures from 50° to 100° C., for exampleat the boiling temperature of the reaction mixture.

The hydrolysis according to process (b), may be effected in accordancewith conventional means for hydrolysing carbamates to produce secondaryamines, for example using acids, such as mineral acids e.g. hydrochloricacid, or using bases such as alkaline hydroxides e.g. potassium orsodium hydroxide. The reaction may be carried out for example in aninert solvent, e.g. a lower alcohol, preferably at the boilingtemperature of the reaction mixture.

The alkylation according to process (c), may be effected in conventionalmanner for the alkylation of secondary amines. The reaction isconveniently carried out in an inert organic solvent, preferably in thepresence of a basic condensation agent, e.g. sodium carbonate, attemperatures from room temperature to about 100° C. In the compounds offormula V, X is for example a halogen atom such as chlorine, bromine oriodine, or the acid residue of an organic sulfonic acid, e.g. analkylsulfonyloxy radical such as methylsulfonyloxy, or anarylsulfonyloxy radical such as phenylsulfonyloxy orp-toluenesulfonyloxy.

The esterification according to process (d) may be effected inconventional manner, e.g. by reaction with an appropriatephysiologically acceptable acid or a reactive functional derivativethereof.

The hydrolysis according to process (e) may also be effected by knownmethods, e.g. in an alkaline medium.

The resulting compounds of the invention may be isolated from thereaction mixture in free base or salt form, and purified in knownmanner. Free base forms may be converted e.g. into acid addition saltforms in conventional manner and vice versa. Suitable acids for saltformation are hydrochloric acid and maleic acid.

The starting materials of formula II may be produced by condensingcompounds of formula VI ##STR6## wherein R₁, R₂ and the ring A are asdefined above, with compounds of formula VII ##STR7## in which R₃ ' isas defined above and "Hal" is a halogen atom, e.g. a chlorine atom, inaccordance with the Grignard method and hydrolysing the obtainedreaction product.

The starting materials of formula III may be obtained by reacting acompound of formula I in which R₃ is methyl, with a compound of formulaVIII

    Hal--COOR.sub.5                                            (VIII)

in which "Hal" and R₅ are as defined above. The reaction is preferablycarried out in an inert solvent, for example an aromatic hydrocarbon,e.g. toluene, and at the boiling temperature of the reaction mixture.

The products of the above reactions may be isolated and purified inknown manner.

Insofar as the preparation of any of the starting materials definedabove is not particularly described, such preparation may be effected inconventional manner or analogously to known methods. Compounds offormula VI are described for example in Elsevier's Encyclopaedia ofOrganic Chemistry, Vol 12A, series III, Elsevier Publishing Company Inc.New York 1948.

In the following Examples all temperatures are given in degrees Celsiusand are uncorrected.

EXAMPLE 1 4-(6-chloro-2,2-dimethyl-indane-1-ylidene)-1-methyl-piperidinehydrochloride

(a) A Grignard reagent is prepared from 14.0 g4-chloro-N-methylpiperidine and 2.6 g magnesium in 200 ml boilingtetrahydrofuran. After cooling, a solution of 10.0 g6-chloro-2,2-dimethyl-indanone in 50 ml tetrahydrofuran is addeddropwise at 5°-10°, and the reaction mixture is refluxed for 6 hours.After cooling, a 10% aqueous solution of ammonium chloride is added andthe mixture is extracted with toluene. The toluene phase is dried andevaporated, to give6-chloro-2,2-dimethyl-1-(1-methyl-4-piperidinyl)indan-1-ol (m.p.181°-182°).

(b) 8.0 g of the compound obtained under (a) are refluxed for 3 hours in100 ml hydrochloric acid in ethanol. The solution is then evaporated andthe residue is recrystallized from ethanol, to give the title compound(m.p. 262°-265°).

The following compounds are obtained in analogous manner from theappropriate starting materials:

(i) 4-(4,6-dichloro-2,2-dimethyl-indane-1-ylidene)-1-methyl-piperidine;and

(ii)bis[4-(2,2,4-trimethyl-indane-1-ylidene)-1-methyl-piperidine]naphtalene-1,5-disulphonate;m.p. 250°-253°.

EXAMPLE 2 4-(2,2-dimethylindane-1-ylidene)piperidine

43 g 4-(2,2-dimethylindane-1-ylidene)-1-methyl-piperidine and 65 g ethylchloroformate in 800 ml toluene are refluxed for 3 hours. After cooling,the solution is washed with 1 N hydrochloric acid and water, dried overmagnesium sulfate and the toluene distilled off. The oily residue isthen refluxed for 6 hours in 90 ml n-butanol and 9 g potassiumhydroxide. The reaction mixture is cooled, filtered, diluted with etherand shaken out with water until neutral. The organic phase is then driedover magnesium sulfate and evaporated, to give the title compound as thehydrogenofumarate: m.p. 200°-202°.

EXAMPLE 32-{2-{2-[4-(2,2,-dimethyl-indane-1-ylidene)piperidine-yl]ethoxy}ethoxy}ethanol

2.5 g 4-(2,2-dimethyl-indane-1-ylidene)-piperidine, 1.95 gtriethyleneglycol-monochlorhydrin and 2 g sodium carbonate in 50 mlmethylisobutylketone are refluxed with stirring for 12 hours. Aftercooling, the reaction mixture is filtered and the filtrate evaporated.The residue is dissolved in ether, the solution washed two times with alittle cold water, dried over sodium sulfate, filtered and evaporated,to give the title compound as a viscous oil. The neutral oxalate meltsat 82°-85°.

Proceding analogously, bis{2-{2-[4-(2,2-dimethyl-indane-1-ylidene)-piperidine-1-yl]ethoxy}ethanol}oxalateis obtained from the appropriate starting materials (m.p. 108°-111°).

The compounds of formula I possess pharmacological activity. Inparticular, the compounds possess anti-anaphylactic activity, and aretherefore useful in the treatment and prophylaxis of allergicconditions, such as allergic asthma, allergic disorders andexersice-induced asthma, as indicated in the passive cutaneousanaphylaxis (PCA) test in the rat after administration of the compoundsat doses from about 0.1 to about 10 mg/kg per os.

The method employed is based on those described by Mota, Immunology 7,681 (1964) and Stofland and Share, J. Physiol. Pharmacol. 52,1114(1974). Female rats (180-200 g) are sensitized by subcutaneousadministration of 1 mg of ovalbumin and 200 mg aluminium hydroxid,dissolved in 1 ml of physiological saline solution and intraperitonealadministration of 0.5 ml of Haemophilus pertussis vaccine(Schweizerisches Serum- und Impf- institut, Bern, Switzerland; 4×10¹⁰organism/ml). Fourteen day later, the animals are decapited, the bloodcentrifuged and the serum (anti-ovalbumin serum) collected and deepfrozen.

The diluted anti-ovalbumin serum is injected intradermally (0.1 ml perinjection site) at three sites on the backs of untreated, female rats.Twenty-four hours after the passive sensitisation, the rats receiveeither solvent or the test compound i.v. in a tail-vein or per os.Immediately afterwards or, in the case of p.o. administration, 60minutes later, the animals receive an intravenous injection of 1 ml ofantigen. The antigen (5 mg/ml) is dissolved in a 0.25% solution of Evansblue dye in physiological saline. In the controls this injection elicitsa cutaneous anaphylactic reaction, the intensity of which isproportional to the distance to which the dye diffuses into the tissuesurrounding the four sensitisation sites. Thirty minutes later, the ratsare killed by CO₂ inhalation and the diameter in mm of the blue spot ateach injection site measured. The drug dose decreasing the diameter ofthe blue area by 50% compared with solvent pretreated control rats(ED50), is obtained from the regression line. The dose-effectcorrelation is tested for statistical significance.

For the above-mentioned use, the dosage will, of course, vary dependingon the compound employed, mode of administration and therapy desired.However, in general, satisfactory results are obtained on administrationat a daily dosage of from about 0.01 to about 10 mg/kg of animal bodyweight, conveniently given in divided doses 2 to 4 times a day or insustained release form. For the larger mammal, the total daily dosage isin the range of from about 1 to about 100 mg, and dosage forms suitablefor oral administration comprise from about 0.25 to about 50 mg of thecompounds admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compound may be administered in free form or e.g. inpharmaceutically acceptable acid addition salt form. Such salt formspossess the same order of activity as the free form and are readilyprepared in conventional manner. Examples of suitable acids for theformation of salts include hydrochlorid acid, oxalic acid, fumaric acidand naphthalene-1,5-disulfonic acid.

In accordance with the foregoing the present invention also provides:

(i) A compound of formula I as hereinbefore defined, in free base or inpharmaceutically acceptable salt form, for use as a pharmaceutical. e.g.for use in the treatment or prophylaxis of allergic conditions, inparticular allergic asthma, allergic disorders and exercise-inducedasthma; as well as

(ii) a pharmaceutical composition comprising a compound of formula I ashereinbefore defined, in free base or in pharmaceutically acceptablesalt form together with a pharmaceutically acceptable diluent or carriertherefor.

What we claim is:
 1. A compound of formula I ##STR8## wherein R₁ and R₂,independently, are C₁₋₄ alkyl,R₃ is hydrogen; C₁₋₄ alkyl; C₃₋₅ alkenyl;C₇₋₁₀ phenylalkyl optionally substituted in the phenyl ring by halogen,C₁₋₄ alkyl or C₁₋₄ alkoxy; or a group of formula (a)

    --(CH.sub.2 --CH.sub.2 --O).sub.n --R.sub.4                (a)

wherein n is an integer of from 1 to 3 and R₄ is hydrogen or a non-toxicacid residue which is removable by hydrolysis under physiologicalconditions, and the ring A is mono-or-di-substituted by fluoro, chloroor C₁₋₄ alkoxy groups, in free base or in pharmaceutically acceptableacid addition salt form.
 2. A compound according to claim 1 wherein R₃is hydrogen or C₁₋₄ alkyl.
 3. A compound according to claim 2 wherein R₃is methyl.
 4. A compound according to claim 1 wherein R₃ is a group offormula (a).
 5. A compound according to claim 1 wherein, when R₃ is agroup of formula (a), R₄ is hydrogen.
 6. A compound according to claim 1wherein ring A is substituted by chloro.
 7. A compound according toclaim 1 which is4-(6-chloro-2,2-dimethyl-indane-1-ylidene)-1-methyl-piperidine in freebase or salt form.
 8. A compound according to claim 1 which is4-(4,6-dichloro-2,2-dimethyl-indane-1-ylidene)-1-methyl-piperidine infree base or salt form.
 9. A compound according to claim 1 which is2-{2-{2-[4-(2,2-dimethyl-indane-1-ylidene)-piperidine-1-yl]-ethoxy}ethoxy}ethanolin free base or salt form.
 10. A compound according to claim 1 which is2-{2-[4-(2,2-dimethyl-indane-1-ylidene)-piperidine-1-yl]-ethoxy}ethanolin free base or salt form.
 11. A method for the treatment or prophylaxisof asthma in a subject in need of such treatment, which method comprisesadministering to said subject an anti-asthma effective amount of acompound according to claim 1 in free base or pharmaceuticallyacceptable acid addition salt form.
 12. A pharmaceutical composition forthe treatment of asthma comprising an anti-asthma effective amount of acompound according to claim 1 in free base or pharmaceuticallyacceptable acid addition salt form, together with a pharmaceuticallyacceptable diluent or carrier therefor.